February 21, 2014

In a recent staff memo, Dr. Robert Temple, Deputy Director for Clinical Science at the FDA's Center for Drug Evaluation and Research (CDER) laid out a new policy in the Manual of Policies and Procedures (MAPP) that FDA staff should follow in reviewing proposed trial designs. This is part of the Department of Health and Human Services' Initiative on Multiple Chronic Conditions. In his memo, Dr. Temple stressed the FDA's interest in encouraging a broad population sample in the development of new drugs.

He writes: "This is reflected in the required (by regulation) analyses of safety and effectiveness by demographic and other relevant subgroups in marketing applications and the recognized concern with possible interactions between treatments and coexisting illnesses and concomitant treatments. FDA and ICH guidance on inclusion of both genders and the elderly also reflects this concern and the documents urge broad patient inclusion. During the interactions that take place between FDA and the sponsor during drug development, FDA should actively encourage the conduct of at least one trial in a broad population that closely resembles the people who will use the drug if it is approved and should discourage unnecessary exclusions."

The new GRP (Good Review Practice) MAPP [Clinical Review of Investigational New Drug Applications] emphasizes that including a broad population in trials needs to become a regular part of the FDA's assessment of individual trials and overall development plans.

Dr. Temple continues: "Apart from attempts to end the routine use of upper age limits in trials, part of our standard procedures should be consideration of why exclusions are needed or appropriate. Where planned exclusions do not meet a test for reasonableness this should be pointed out to sponsors and protocol modifications should be encouraged. The goal is for us to become more cognizant of exclusion criteria, to examine such criteria closely, and to encourage removal of exclusions that are unnecessary."

FDA is concerned that drug development studies will not provide evidence of the effects of treatment in the "real world." This has led to the concept, as Dr. Temple describes, of "effectiveness" as opposed to "efficacy" trials and to a call for "pragmatic" trials, generally focused on enrolling a patient population closer to the population likely to be treated when the drug is marketed.

FDA recognizes in its Enrichment Guidance that careful patient selection (prognostic and predictive enrichment, encouraging compliance) can enhance study power, but enrichment does not necessitate a general exclusion of older patients, people with concomitant illness, etc., unless these factors will lead to patient drop-outs or use of medication(s) that interfere with the test drug, which will not usually be the case. We share the concern that unnecessary exclusions lead to the study of treatment populations that are not representative of the people who will use the drug if it is approved, particularly with respect to demographic characteristics, concomitant illnesses and concomitant therapies.

FDA contributes to a work group including NIH, CDC, CMS, AHRQ, and others, with the focus on identifying barriers to enrollment of patients with multiple chronic conditions in clinical trials and to increasing the numbers of such patients in future trials. One FDA contribution to this effort, supported by FDA and the HHS Assistant Secretary for Planning and Evaluation (ASPE), Office of Science and Data Policy, was a study by Digital Infuzion of the exclusions from controlled trials. The study assessed data from clinical trials submitted in drug and biologic licensing applications (NDAs and BLAs) with electronic data during 2010, encompassing a total 147 studies and over 115,000 subjects. The studies were examined for both explicit exclusion criteria in the protocol (e.g., history of psychiatric disorder) and for the concomitant illnesses present in patients in the completed studies.

Dr. Temple continued, describing several key findings of the study:

71% of studies excluded patients with a psychiatric disorder (presumably specific disorders, not all psychiatric disorders)

In his concluding comments, Dr. Temple notes: "both HHS and FDA have an interest in encouraging inclusion of a broad range of patients, specifically, patients with chronic conditions other than the one being studied, and patients of more advanced age, as well as a broader interest in minimizing exclusions, i.e., so-called "pragmatic" trials."